Although the 'reverse genetics' approach has associated SLE disease risk with several genes with known immune function including complement proteins, antibody receptors and immune signaling molecules, the newly developed ability to scan the entire genome provides an unprecedented opportunity for novel discovery of critical pathways in disease pathogenesis. SLEGEN, a productive multi-institutional consortium of lupus investigators, matches the capacity for current state-of-the-art genome-wide technology with large phenotypically characterized participant collections which provide appropriate statistical power for genomewide studies. SLEGEN has successfully conducted a genome wide association study (GWAS) with independent replication in European-derived populations and has both confirmed previous candidate genes and discovered multiple new genetic effects. As a result of SLEGEN, and the work of others, the genetic variants known to contribute to the risk of lupus now include ITGAM (CDI lb, CR3), STAT4, BANKl, BLK, HLA-DR, IRF5, FCGR3A, FCGR2A, Clq, Complement C4, and PTPN22, among others. However, both the phenotypic variation in other populations with different ancestries and initial data indicate that not all European variants have similar roles in these populations and that we have much to learn about the genetic architecture of human lupus. A trans-racial mapping approach provides a unique opportunity to identify both variants in common and variants which may be population specific. SLEGEN is uniquely positioned to take advantage of this opportunity. Project 1 will explore the HLA region variation in >6000 subjects who are African-American, Amerindian admixed Hispanics, or Asians and grounded at HLA-DRB2 using existing genome data for European-derived subjects. Projects 2-4 will explore the whole genome by evaluating 1.8 million markers in 6000 non-European subjects with replication, fine mapping, and trans-racial mapping in 9000 additional subjects. This will be the largest genomic exploration attempted in lupus, and in aggregate, will benefit from genetic data assembled from >27,000 cases and controls. These experiments are highly interdependent, relying upon inferences in one population group for perspective and interpretation in the others. The resulting level of understanding promises to establish the genetic etiology of lupus, spawn new diagnostics, prognostics, and therapeutics which provide therapeutic benefit to this and many related illnesses.